HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice.

Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1(-/-) mouse phenotype. The missense variant is predicted to result in the substitution of a cysteine for an arginine at amino acid residue 207 (Arg207Cys), which corresponds to the highly conserved Arg5 of the homeodomain. Arg5 interacts with thymine in the minor groove of DNA through hydrogen bonding and electrostatic attraction. Molecular modeling and an in vitro DNA-protein binding assay predict that the mutation would disrupt these interactions, destabilize the HOXB1:PBX1:DNA complex, and alter HOXB1 transcriptional activity.

Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome.

OBJECTIVE: To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort. DESIGN: Prospective, observational study. PARTICIPANTS: Attendees of 3 consecutive Moebius syndrome conferences held in the United States, with a prior diagnosis of Moebius syndrome, were invited to participate. METHODS: Participants underwent standardized ophthalmologic examination for Moebius syndrome minimum diagnostic criteria (MDC) (congenital, nonprogressive facial palsy, and abduction deficit) and genetic testing for HOXA1, HOXB1, and TUBB3 mutations. MAIN OUTCOME MEASURES: The number of patients meeting MDC and the number of patients with confirmed genetic mutation. RESULTS: A total of 112 participants from 107 families enrolled. Nineteen percent of participants (21/112) did not meet accepted MDC for Moebius syndrome because they had abduction deficits without facial palsy or facial palsy with full ocular motility. All 5 families with 2 affected individuals had at least 1 family member in this category, including 2 siblings with comitant strabismus who harbored a HOXB1 mutation. Four unrelated participants, also not meeting MDC, had large-angle exotropia, vertical gaze deficiency, and ptosis consistent with congenital fibrosis of the extraocular muscles type 3 (CFEOM3); 1 patient harbored a novel TUBB3 mutation, and 3 patients harbored previously reported de novo TUBB3 mutations. Three percent of participants (3/112) met MDC but also had restricted vertical gaze. The remaining 88 participants (79%) met MDC and had full vertical gaze. This group had relatively homogeneous findings, and none had a family history of Moebius syndrome. Two previously undescribed phenomena were observed in this category: (1) volitional Bell's phenomenon and (2) intorsion with fixation. CONCLUSIONS: Although the genetic contributors to classic Moebius syndrome remain elusive, accuracy in clinical evaluation will properly subdivide patients to facilitate genetic testing as new candidate genes are identified. Failure to test ocular motility may lead to misdiagnosis of Moebius syndrome, especially in patients who have facial palsy with full ductions. Patients with exotropia, vertical gaze limitation, and ptosis do not have classic Moebius syndrome and may have TUBB3 mutations associated with CFEOM3. To optimize genetic analysis, we propose adding "full vertical motility" to the MDC for Moebius syndrome.

A novel syndrome caused by the E410K amino acid substitution in the neuronal ß-tubulin isotype 3.

Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein ß-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site. We report the detailed phenotypes of eight unrelated individuals who harbour this de novo mutation, and thus define the 'TUBB3 E410K syndrome'. Individuals harbouring this mutation were previously reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay and possible peripheral neuropathy. We now confirm by electrophysiology that a progressive sensorimotor polyneuropathy does indeed segregate with the mutation, and expand the TUBB3 E410K phenotype to include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), stereotyped midface hypoplasia, intellectual disabilities and, in some cases, vocal cord paralysis, tracheomalacia and cyclic vomiting. Neuroimaging reveals a thin corpus callosum and anterior commissure, and hypoplastic to absent olfactory sulci, olfactory bulbs and oculomotor and facial nerves, which support underlying abnormalities in axon guidance and maintenance. Thus, the E410K substitution defines a new genetic aetiology for Moebius syndrome, Kallmann syndrome and cyclic vomiting. Moreover, the c.1228G>A mutation was absent in DNA from ∼600 individuals who had either Kallmann syndrome or isolated or syndromic ocular and/or facial dysmotility disorders, but who did not have the combined features of the TUBB3 E410K syndrome, highlighting the specificity of this phenotype-genotype correlation. The definition of the TUBB3 E410K syndrome will allow clinicians to identify affected individuals and predict the mutation based on clinical features alone.

HOXA1 Mutations are Not Commonly Associated with Non-Syndromic Deafness.

OBJECTIVE: Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness. METHODS: Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing. RESULTS: All 48 probands had normal neuro-ophthalmologic and general medical examinations except for refractive errors. All had congenital non-syndromic sensorineural hearing loss that was symmetric bilaterally and profound (>90 dBHL) in 33 individuals and varied from 40 to 90 dBHL in the remainder. Thirty-nine of these individuals had neuroimaging studies, all documenting normal internal carotid arteries and normal 6th, 7th, and 8th cranial nerves bilaterally. Of these, 27 had normal internal ear structures with the remaining 12 having mild to modest developmental abnormalities of the cochlea, semicircular canals, and/or vestibular aqueduct. No patient had homozygous HOXA1 mutations. CONCLUSIONS: None of these patients with non-syndromic deafness had HOXA1 mutations. None had major inner ear anomalies, obvious cerebrovascular defects, or recognized congenital heart disease. HOXA1 is likely not a common cause of non-syndromic deafness in this Middle Eastern population.

Neurologic injury in isolated sulfite oxidase deficiency.

BACKGROUND: We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD). METHODS: All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed. RESULTS: Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients. CONCLUSIONS: ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.Lésions neurologiques dans le déficit isolé en sulfite oxydase.

Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development.

We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.

A newly recognized autosomal recessive syndrome affecting neurologic function and vision.

Genetic factors represent an important etiologic group in the causation of intellectual disability. We describe a Saudi Arabian family with closley related parents in which four of six children were affected by a congenital cognitive disturbance. The four individuals (aged 18, 16, 13, and 2 years when last examined) had motor and cognitive delay with seizures in early childhood, and three of the four (sparing only the youngest child) had progressive, severe cognitive decline with spasticity. Two affected children had ocular malformations, and the three older children had progressive visual loss. The youngest had normal globes with good functional vision when last examined but exhibited the oculodigital sign, which may signify a subclinical visual deficit. A potentially deleterious nucleotide change (c.1A>G; p.Met1Val) in the C12orf57 gene was homozygous in all affected individuals, heterozygous in the parents, and absent in an unaffected sibling and >350 normal individuals. This gene has no known function. This family manifests a autosomal recessive syndrome with some phenotypic variability that includes abnormal development of brain and eyes, delayed cognitive and motor milestones, seizures, and a severe cognitive and visual decline that is associated with a homozygous variant in a newly identified gene.

Congenital cranial dysinnervation disorders: a concept in evolution.

PURPOSE OF REVIEW: We review the congenital and genetic diagnoses that are currently included in the congenital cranial dysinnervation disorders (CCDDs). RECENT FINDINGS: Recent literature contains new genotypic and phenotypic descriptions of Duane retraction syndrome, Moebius syndrome, and other CCDDs. New genes which when mutated can result in CCDD have been identified, permitting a better understanding of associated phenotypes. More information is available regarding neurodevelopmental and clinical effects of various gene mutations associated with individual CCDDs. For certain CCDDs, the phenotype of a particular individual may not completely predict the genotype, and conversely, the genotype may not always predict the phenotype. SUMMARY: The CCDD concept has focused attention on specific congenital disturbances of human ocular motility and on the fact that these disorders are typically neurogenic in origin. The past decade has seen rapid evolution within this field with the last 2 years yielding additional information about existing diagnoses, genes, and phenotypes that may result in better classification of these disorders and new genotype-phenotype correlations in the future.

Variable ptosis after botulinum toxin type a injection with positive ice test mimicking ocular myasthenia gravis.

We describe a patient who received cosmetic botulinum toxin type A injections to the brow and subsequently developed unilateral ptosis that was variable during examination and was transiently improved after the ice pack test. Ptosis gradually resolved spontaneously over approximately 3 months. This is the third patient to have variable ptosis documented after botulinum toxin type A injection to the brow and the second to have a positive ice test. The ice test is not completely specific for myasthenia gravis but may, at times, improve ptosis resulting from other defects at the neuromuscular junction. Wound botulism now is much more common because of illicit drug use, and the ice test also might be positive in this setting.

Visual loss in orbitofacial neurofibromatosis type 1.

PURPOSE: On occasion, neurofibromas in neurofibromatosis type 1 may be present on the lid, brow, or face of an infant or child, a circumstance commonly referred to as "orbitofacial neurofibromatosis" (OFNF). The present study evaluates the causes and extent of visual loss in a group of patients with OFNF. DESIGN: Case series. PARTICIPANTS: Fifty-five patients with OFNF. METHODS: Retrospective medical record review and reexamination of selected patients from one institution. MAIN OUTCOME MEASURES: Visual acuity and identification of underlying cause of reduced vision. RESULTS: Fifty patients with unilateral OFNF (23 male, 27 female, aged 4-48 years at last visit) and 5 patients with bilateral OFNF (2 male, 3 female, aged 15-43 years) had adequate information available to assess afferent visual functioning. Nine patients (4 male, 5 female, aged 4-28 years) had optic pathway glioma (OPG) in addition to OFNF. Patients were followed as long as 27 years (mean 8.4 years). Thirty-nine patients (71% of total) had visual acuity of ≤20/60 on the side of OFNF involvement (or the side of worse OFNF involvement in patients with bilateral disease). One or more causes of amblyopia were present in 29 of these patients, 19 patients had organic disease of the eye (e.g., glaucoma or retinal detachment) or the afferent system (e.g., OPG), and 12 patients had correctable refractive errors. CONCLUSIONS: Visual loss in this OFNF cohort was common, typically profound, and usually multifactorial. Some causes of visual loss (including congenital glaucoma with buphthalmos and retinal detachment, disconjugate gaze due in part to distorted skull development causing strabismic amblyopia, and OPG) were difficult to treat adequately and tended to cause progressive, profound visual loss. Therefore, careful observation should be made during the period of visual immaturity for possible causes of amblyopia that might be treatable, such as refractive changes, occlusion of the visual axis, or congenital glaucoma. As affected individuals get older, physicians must be vigilant for the progression of optic nerve disease due to glaucoma or OPG and to the possibility that vision might be improved by refraction.

The neurology of carbonic anhydrase type II deficiency syndrome.

Carbonic anhydrase type II deficiency syndrome is an uncommon autosomal recessive disease with cardinal features including osteopetrosis, renal tubular acidosis and brain calcifications. We describe the neurological, neuro-ophthalmological and neuroradiological features of 23 individuals (10 males, 13 females; ages at final examination 2-29 years) from 10 unrelated consanguineous families with carbonic anhydrase type II deficiency syndrome due to homozygous intron 2 splice site mutation (the 'Arabic mutation'). All patients had osteopetrosis, renal tubular acidosis, developmental delay, short stature and craniofacial disproportion with large cranial vault and broad forehead. Mental retardation was present in approximately two-thirds and varied from mild to severe. General neurological examinations were unremarkable except for one patient with brisk deep tendon reflexes and two with severe mental retardation and spastic quadriparesis. Globes and retinae were normal, but optic nerve involvement was present in 23/46 eyes and was variable in severity, random in occurrence and statistically correlated with degree of optic canal narrowing. Ocular motility was full except for partial ductional limitations in two individuals. Saccadic abnormalities were present in two, while half of these patients had sensory or accommodative strabismus, and seven had congenital nystagmus. These abnormalities were most commonly associated with afferent disturbances, but a minor brainstem component to this disorder remains possible. All internal auditory canals were normal in size, and no patient had clinically significant hearing loss. Neuroimaging was performed in 18 patients and repeated over as long as 10 years. Brain calcification was generally progressive and followed a distinct distribution, involving predominantly basal ganglia and thalami and grey-white matter junction in frontal regions more than posterior regions. At least one child had no brain calcification at age 9 years, indicating that brain calcification may not always be present in carbonic anhydrase type II deficiency syndrome during childhood. Variability of brain calcification, cognitive disturbance and optic nerve involvement may imply additional genetic or epigenetic influences affecting the course of the disease. However, the overall phenotype of the disorder in this group of patients was somewhat less severe than reported previously, raising the possibility that early treatment of systemic acidosis with bicarbonate may be crucial in the outcome of this uncommon autosomal recessive problem.

Molecular and neurological characterizations of three Saudi families with lipoid proteinosis.

BACKGROUND: Lipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood. It is caused by homozygous or compound heterozygous mutations in the ECM1 gene. The disease is largely uncharacterized in Arab population and the mutation(s) spectrum in the Arab population is largely unknown. We report the neurologic and neuroradiologic characteristics and ECM1 gene mutations of seven individuals with lipoid proteinosis (LP) from three unrelated consanguineous families. METHODS: Clinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene. RESULTS: All seven affected individuals had skin scarring and hoarseness from early childhood. The two children in Family 1 had worse skin involvement and worse hoarseness than affected children of Families 2 and 3. Both children in Family 1 were modestly mentally retarded, and one had typical calcifications of the amygdalae on CT scan. Affected individuals in Families 2 and 3 had no grossneurologic, neurodevelopmental, or neuroimaging abnormalities. Skin histopathology was compatible with LP in all three families. Sequencing the full coding region of ECM1 gene revealed two novel mutationsin Family 1 (c.1300-1301delAA) and Family 2 (p.Cys269Tyr) and in Family 3 a previously described 1163 bp deletion starting 34 bp into intron 8. CONCLUSIONS: These individuals illustrate the neurologic spectrum of LP, including variable mental retardation, personality changes, and mesial temporal calcificationand imply that significant neurologic involvement may be somewhat less common than previously thought. The cause of neurologic abnormalities was not clear from either neuroimaging or from what is known about ECM1 function. The severity of dermatologic abnormalities and hoarseness generally correlated with neurologic abnormalities, with Family 1 being somewhat more affected in all spheres than the other two families. Nevertheless, phenotype-genotype correlation was not obvious, possibly because of difficulty quantifying the neurologic phenotype and because of genetic complexity.

Recent progress in understanding congenital cranial dysinnervation disorders.

BACKGROUND: In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substitute for the traditional concept of congenital fibrosis of the extraocular muscles (CFEOM) based on mounting genetic, neuropathologic, and imaging evidence, suggesting that many, if not all, of these disorders result from a primary neurologic maldevelopment rather than from a muscle abnormality. This report provides an update 8 years after that original report. EVIDENCE ACQUISITION: Review of pertinent articles published from January 2003 until June 2010 describing CCDD variants identified under PubMed MeSH terms congenital fibrosis of the extraocular muscles, congenital cranial dysinnervation disorders, individual phenotypes included under the term CCDD, and congenital ocular motility disorders. RESULTS: At present, a total of 7 disease genes and 10 phenotypes fall under the CCDD umbrella. A number of additional loci and phenotypes still await gene elucidation, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuroimaging, have expanded our understanding of the mechanisms underlying several anomalous eye movement patterns. CONCLUSIONS: Current evidence still supports the concept that the CCDDs are primarily due to neurogenic disturbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cerebrovascular, cardiovascular, and skeletal abnormalities.

Congenital myasthenic syndrome due to homozygous CHRNE mutations: report of patients in Arabia.

We describe the clinical characteristics of 3 siblings from 1 family with congenital myasthenic syndrome due to homozygous mutations of the gene coding for the epsilon subunit of the acetylcholine receptor (CHRNE). Onset of symptoms occurred in the first few months of life with ptosis, restricted ocular motility, mild proximal weakness, and difficulty swallowing. Multiple hospital admissions were required due to recurrent pulmonary infections. There was no decremental conduction on repetitive nerve stimulation, but jitter was increased on single fiber electromyographic. Since early childhood, our patients have done well without pulmonary or bulbar symptoms and with partial improvement on pyridostigmine therapy. Response of ptosis to diagnostic ice pack test was striking. Although these siblings have a clinical history and examination findings typical of homozygous CHRNE mutations, the clinical presentation of congenital myasthenia subtypes is variable, and accurate genotyping is essential in choosing the appropriate treatment.

Long-term results of an intraoperative adjustable superior oblique tendon suture spacer using nonabsorbable suture for Brown Syndrome.

OBJECTIVE: To investigate the long-term surgical outcome of Brown syndrome using an intraoperative adjustable superior oblique (SO) tendon suture spacer. DESIGN: Retrospective case series. PARTICIPANTS: Thirteen patients with congenital unilateral Brown syndrome operated on at the Wolfe Eye Clinic from 2001 through 2007. METHODS: Retrospective analysis of consecutive patients managed with the SO suture spacer followed up for at least 10 months. MAIN OUTCOME MEASURES: Surgical intervention for patients having severe or moderate forms of Brown syndrome. Postoperative effect on abnormal head posture, vertical strabismus in primary gaze, vertical strabismus into affected side gaze, and elevation in adduction. RESULTS: The mean duration of follow-up was 30 months (range, 10-72 months). Abnormal head posture improved from 13 degrees (range, 0 degrees -30 degrees ) to 0.4 degrees (range, 0 degrees -5 degrees ). Vertical strabismus in primary gaze improved from -10Delta (range, 0Delta to -35Delta) to 2.8Delta (range, -16Delta to 16Delta). Vertical in side gaze improved from -20Delta (range, -35Delta to -8Delta) to -1.5Delta (range, -20Delta to 18Delta). Elevation in adduction improved from -3.5 (range, -4 to -2) to -0.4 (range, -2 to 4). Four patients had an overcorrection and 2 patients experienced an increasing late effect. In no patient did a late under correction develop. CONCLUSIONS: The SO suture spacer procedure alleviated abnormal head positions in patients with Brown syndrome by improving vertical strabismus in primary position and in the affected field of gaze while avoiding overcorrection in contralateral gaze. The benefits of the procedure persisted over time.

Bilateral synergistic convergence associated with homozygous ROB03 mutation (p.Pro771Leu).

OBJECTIVE: To document the phenotype and determine the genotype of a child with synergistic convergence. DESIGN: Interventional case report. PARTICIPANTS: Patient and nuclear family (7 members total). METHODS: Ophthalmologic, neurologic, and radiologic examination of the proband; venous blood sampling for candidate gene testing of the proband; venous blood sampling for confirmatory testing in other family members. MAIN OUTCOME MEASURES: Clinical and radiologic observations in proband and candidate gene results. RESULTS: The proband, a 9-year-old girl, substituted convergence for horizontal gaze (synergistic convergence) since birth. She also had conjugate pendular nystagmus, asynchronous blinking, and high myopia. No family member had ophthalmologic or medical symptoms. Neuroradiologic imaging revealed hindbrain dysplasia and modest scoliosis. Sequencing of ROB03, the gene associated with horizontal gaze palsy and progressive scoliosis, revealed a novel missense mutation (p.Pro771Leu) that altered an evolutionarily conserved amino acid. Screening the family for this mutation confirmed that both parents were carriers and identified 2 sisters as carriers and 2 brothers as noncarriers. CONCLUSIONS: This is the second reported patient with synergistic convergence and the first associated with a documented pathologic genotype. Unlike the previously reported case (which occurred in the setting of the cranial dysinnervation disorder congenital fibrosis of the extraocular muscles), our patient presumably has a supranuclear cause. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ophthalmic features of Joubert syndrome.

PURPOSE: Joubert syndrome (Online Mendelian Inheritance in Man 213300) is a rare autosomal recessive congenital malformation of the brainstem and cerebellar vermis. Diagnosis is based on characteristic clinical features (e.g., hypotonia, episodic hyperpnea, developmental delay, progressive ataxia) and is confirmed by distinctive neuroradiologic findings (e.g., the "molar tooth" sign). Variable ophthalmic features have been mentioned in prior reports; however, most do not detail eye findings and the few that do were before the publication of suggested diagnostic criteria. The objective of the current study is to describe the ophthalmic phenotype in a cohort of patients with Joubert syndrome for whom the diagnosis was made using current diagnostic criteria. DESIGN: Prospective case series. PARTICIPANTS: Eight children diagnosed clinically with radiologic confirmation. METHODS: Ophthalmic examination and visual electrophysiology. MAIN OUTCOME MEASURES: Ocular and oculomotor examination (as allowed by patient cooperation), electroretinography, flash visual-evoked potential (fVEP). RESULTS: Patients' ages ranged from 7 months to 10 years. Saccadic dysfunction was observed in all cooperative patients (6/6); compensatory head thrusts or turns were present in all except the youngest patient (7 months of age). Most patients (5/8) had primary-position nystagmus (see-saw in 3/5). Abnormal pursuit (3/7) and a dystrophic retinal appearance (3/8) were also seen. One patient had bilateral asymmetric ptosis with unilateral lid elevation during ipsilateral abduction. Electroretinography findings were normal for all 8 patients. Seven patients underwent fVEP; 6 were abnormal (asymmetric) and one was not interpretable because of study artifact. CONCLUSIONS: Ophthalmologists should be aware that saccadic dysfunction (typically with head thrusts) and primary position nystagmus (typically see-saw) in a developmentally delayed child suggest the diagnosis of Joubert syndrome, especially if a dystrophic retinal appearance is also present. Our findings of asymmetric fVEPs and see-saw nystagmus suggest an abnormality in optic nerve decussation, consistent with the concept that impaired axonal guidance occurs in patients with Joubert syndrome. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The clinical spectrum of homozygous HOXA1 mutations.

We describe nine previously unreported individuals from six families who have homozygous mutations of HOXA1 and either the Bosley-Salih-Alorainy syndrome (BSAS) or the Athabascan brainstem dysgenesis syndrome (ABDS). Congenital heart disease was present in four BSAS patients, two of whom had neither deafness nor horizontal gaze restriction, thus raising the possibility that cardiovascular malformations might be a clinically isolated, or relatively isolated, manifestation of homozygous HOXA1 mutations. Two ABDS probands had relatively mild mental retardation. These individuals blur the clinical distinctions between the BSAS and ABDS HOXA1 variants and broaden the phenotype and genotype of the homozygous HOXA1 mutation clinical spectrum.

Ophthalmoplegia and Congenital Cranial Dysinnervation Disorders.

Some forms of ophthalmoplegia are congenital and fall into the category of Congenital Cranial Dysinnervation Disorders (CCDDs). These disorders arise from a primary defect of cranial nucleus/nerve development or guidance. Many have substantial limitations of ocular motility with or without other associated features. The type and degree of ophthalmoplegia can be similar between CCDD subtypes as well as with non-congenital forms of ophthalmoplegia. Therefore diagnostic confirmation often requires neuro-imaging and/or genetic investigations. The clinician should consider this category in cases of ophthalmoplegia that are congenital and nonprogressive in nature.